INSIGHT: A phase 3, randomized, multicenter, open-label study of ripretinib vs sunitinib in patients with advanced gastrointestinal stromal tumor previously treated with imatinib harboring <i>KIT</i> exon 11 + 17 and/or 18 mutations.
Authors: Suzanne George, Jean-Yves Blay, Ping Chi, Robin Lewis Jones, Cesar Serrano, Neeta Somaiah, William Reichmann, Kam Sprott, Haroun Achour, Matthew L. Sherman, Rodrigo Ruiz-Soto, Michael C. Heinrich, Sebastian Bauer
Journal: Journal of Clinical Oncology (2023)

TPS11582 Background: Gastrointestinal stromal tumor (GIST) is the most common gastrointestinal sarcoma, with approximately 80% of cases driven by KIT mutations. Most patients (pts) with advanced GIST develop disease progression following first-line treatment with imatinib due to KIT secondary resistance mutations occurring most commonly in the ATP-binding pocket (exons 13/14) and/or activation loop (exons 17/18). Sunitinib is approved as second-line therapy for advanced GIST. Ripretinib is a switch-control tyrosine kinase inhibitor approved for pts with GIST who received prior treatment with 3 or more kinase inhibitors, including imatinib. In the phase 3 INTRIGUE study (NCT03673501) in second-line advanced GIST, ripretinib was not superior to sunitinib in terms of progression-free survival (PFS); however, a more favorable safety profile was observed with ripretinib vs sunitinib (Bauer S et al. J Clin Oncol. 2022). Exploratory mutational analysis from INTRIGUE using baseline circulating tumor DNA (ctDNA) demonstrated that pts harboring primary KIT exon 11 mutations with secondary resistance mutations exclusively in KIT exons 17 and/or 18 derived PFS benefit with ripretinib vs sunitinib (median, 14.2 vs 1.5 months; HR = 0.22, 95% CI 0.11 to 0.44, nominal P &lt; 0.0001; Bauer S et al. J Clin Oncol. 2023; abstract 397784). Here, we describe a planned phase 3 study for pts with advanced GIST previously treated with imatinib harboring KIT exon 11 + 17 and/or 18 mutations. Methods: INSIGHT is a phase 3, randomized, open-label study that aims to evaluate the efficacy of ripretinib vs sunitinib in pts with advanced GIST previously treated with imatinib and who harbor KIT exon 11 + 17 and/or 18 mutations. Eligible pts must be ≥18 years old with histologically confirmed GIST and co-occurring KIT exon 11 + 17 and/or 18 mutations confirmed by ctDNA analysis. Pts must also have advanced disease with ≥1 measurable lesion per modified Response Evaluation Criteria in Solid Tumors (mRECIST) v1.1, radiologic progression on imatinib, and an Eastern Cooperative Oncology Group Performance Status ≤2. Key exclusion criteria include a KIT exon 9, 13, or 14 mutation via ctDNA at screening and prior treatment with another line of therapy in addition to imatinib for advanced GIST. A total of 54 pts will be randomized (2:1) to receive ripretinib 150 mg once daily (QD; continuous) or sunitinib 50 mg QD (4 weeks on/2 weeks off) in 6-week cycles. The primary endpoint is PFS by independent radiologic review (IRR) per mRECIST v1.1; key secondary endpoints are objective response rate by IRR using mRECIST v1.1 and overall survival. Safety and patient-reported outcome measures will also be assessed. Pts randomized to the sunitinib arm may cross over to the ripretinib arm upon disease progression. Clinical trial information: NCT05734105 .